Inoue Akitomo, Outani Hidetatsu, Imura Yoshinori, Nakai Sho, Takami Haruna, Kotani Yuki, Mae Hirokazu, Okada Seiji
Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
Cancer Sci. 2025 Apr;116(4):976-989. doi: 10.1111/cas.16438. Epub 2025 Jan 9.
Effective therapeutic strategies for epithelioid sarcoma (EpS), a high-grade soft tissue sarcoma characterized by loss of integrase interactor 1 (INI1), have not yet been developed. The present study therefore investigated the association between INI1 loss and upregulation of the aurora kinase A (AURKA)/polo-like kinase 1 (PLK1)/cell division cycle 25C (CDC25C) axis, as well as the therapeutic relevance of this axis in EpS. Notably, our findings showed that the reintroduction of INI1 in VA-ES-BJ cells significantly reduced proliferation, mitigated tumorigenicity, and negatively regulated the expression of AURKA and its downstream effectors, as well as the activation of PLK1 and CDC25C. These results suggest that INI1 deficiency enhanced EpS growth by upregulating the AURKA/PLK1/CDC25C axis. AURKA silencing using siRNAs inhibited VA-ES-BJ and Asra-EPS cell proliferation by inactivating PLK1 and CDC25C. Alisertib, a selective AURKA inhibitor, exerted markedly greater antiproliferative effects on EpS cells than on normal human dermal fibroblasts, and these effects were dependent on INI1 deficiency. Inhibition of AURKA activity by alisertib induced G2/M cell cycle arrest and apoptosis via the inactivation of AURKA downstream effectors in EpS cells. Alisertib also significantly decreased VA-ES-BJ xenograft tumor growth. Taken together, our findings revealed that INI1 loss in EpS cells enhances the expression of AURKA and its downstream effectors and persistently activates PLK1 and CDC25C mediated by AURKA, making the cells reliant on the AURKA/PLK1/CDC25C axis. Therefore, the AURKA/PLK1/CDC25C axis activated by INI1 deficiency could serve as a novel therapeutic target for this devastating disease.
上皮样肉瘤（EpS）是一种高级别软组织肉瘤，其特征为整合酶相互作用因子1（INI1）缺失，目前尚未开发出有效的治疗策略。因此，本研究调查了INI1缺失与极光激酶A（AURKA）/ polo样激酶1（PLK1）/细胞分裂周期25C（CDC25C）轴上调之间的关联，以及该轴在EpS中的治疗相关性。值得注意的是，我们的研究结果表明，在VA-ES-BJ细胞中重新引入INI1可显著降低细胞增殖、减轻致瘤性，并负向调节AURKA及其下游效应分子的表达，以及PLK1和CDC25C的激活。这些结果表明，INI1缺陷通过上调AURKA/PLK1/CDC25C轴促进了EpS的生长。使用小干扰RNA（siRNA）沉默AURKA可通过使PLK1和CDC25C失活来抑制VA-ES-BJ和Asra-EPS细胞的增殖。alisertib是一种选择性AURKA抑制剂，对EpS细胞的抗增殖作用明显大于对正常人皮肤成纤维细胞的作用，且这些作用依赖于INI1缺陷。alisertib抑制AURKA活性可通过使EpS细胞中AURKA下游效应分子失活来诱导G2/M期细胞周期阻滞和凋亡。alisertib还显著降低了VA-ES-BJ异种移植瘤的生长。综上所述，我们的研究结果表明，EpS细胞中INI1缺失会增强AURKA及其下游效应分子的表达，并持续激活由AURKA介导的PLK1和CDC25C，使细胞依赖于AURKA/PLK1/CDC25C轴。因此，由INI1缺陷激活的AURKA/PLK1/CDC25C轴可作为这种毁灭性疾病的一个新的治疗靶点。
